image: Mouse parvalbumin neurons. Parvalbumin neurons are affected by oxidative stress in mouse model of schizophrenia. Markers of this neuropathological process can be detected in the blood of human patients, helping to diagnose and potentially treat them with antioxidant compounds. view more
Credit: @UNIL/CHUV Inès Khadimallah
Psychotic symptoms are a characteristic clinical manifestation of schizophrenia. They go hand-in-hand with an increase in oxidative stress, which results in a damage of a particular type of neurons, called parvalbumin neurons. This deterioration leads to a dysfunction in the activity of the prefrontal cortex, a region of the brain that is involved in cognition. A study conducted at the Centre for Psychiatric Neuroscience of the Lausanne University (UNIL) and the Lausanne University Hospital (CHUV), and supported by the National Centre of Competences in Research Synapsy (Synapsy), has shown, in an animal model, that the cellular mechanism for recycling mitochondria is deficient in parvalbumin neurons. The study – published in the journal Molecular Psychiatry – investigated the underlying biochemical mechanisms, pinpointing two key molecules, miR-137 and COX6A2, that can be detected in blood. When used as biomarkers in patients diagnosed with psychosis, they allow to determine two distinct clinical sub-groups with different severity of symptoms, of cognitive deficits and functioning in everyday life. This discovery represents a major breakthrough for stratifying individuals suffering from schizophrenia, whose heterogeneity of symptoms currently restricts diagnosis and treatment.
Schizophrenia is a psychiatric disorder whose clinical manifestations are extremely heterogeneous, which makes diagnosis difficult, and suggests that several neurobiological mechanisms are involved. Patient stratification, based on reliable biomarkers, would allow to better target available treatment options. To this end, Kim Do's group, researcher at UNIL/CHUV Centre for Psychiatric Neuroscience, in collaboration with Philippe Conus, director of the CHUV Service of General Psychiatry, carried out a translational study in patients and experimental model, focusing on the mitochondria of the parvalbumin neurons.
The central role of oxidative stress
Mitochondria are organelles responsible for producing the energy cells need to function normally. They use oxygen to do this, releasing highly toxic molecules called "free radicals. These have to be eliminated to avoid irremediable damage by oxidation, i.e. oxidative stress. The antioxidant system takes on this task. The brain, an important producer of free radicals, is very sensitive to deregulations of the antioxidant system. "We know that an essential antioxidant produced by the human body, called glutathione, is deficient in schizophrenic patients", explains Kim Do. "This deficiency and the resulting imbalance between free radicals and antioxidants (called redox dysregulation) lead, among other consequences, to an alteration of parvalbumin neurons, a type of neurons that is directly involved in all cognitive functions".
To conduct its studies, Professor Do’s group works with an animal model of schizophrenia, in which the level of cerebral glutathione is lowered. "This animal model is not designed to mimic a human disease in all its complexity, but to reproduce a typical abnormality and investigate its consequences."
Biomarkers of impaired mitochondria in parvalbumin neurons
Thanks to this animal model, it has been possible to observe that impaired mitochondria accumulate in parvalbumin neurons in the prefrontal cortex. "Normally, they’re eliminated or recycled, so that the "cleaning system" is no longer functional" adds Inès Khadimallah, a research fellow at Professor Do's laboratory and first author of the article published in Molecular Psychiatry.
Mitochondria are generally able to eliminate their damaged parts by splitting, using a mechanism called mitophagy. This process involves a series of molecules whose production is controlled by miR137, a microRNA that plays a key role in their regulation. Inès Khadimallah, in collaboration with her colleagues, succeeded in demonstrating that the level of miR-137 was very high in the model, as was oxidative stress. In parallel, an element of cellular respiration expressed specifically by parvalbumin neurons, the COX6A2 molecule is decreased. "In other words, the mitochondria of parvalbumin neurons are dysfunctional following the increase in oxidative stress, and it can be shown through analyzing the levels of miR-137 and COX6A2 in the blood".
On the way to an innovative treatment?
In their attempts to intervene directly on the free radicals produced by mitochondria, the neuroscientists showed, in the animal model, that the alterations of these two molecules, miR137 and COX6A2, can be completely corrected by an antioxidant compound that specifically targets mitochondria, called MitoQ. The research team was able to demonstrate that treatment with MitoQ also increases the survival and functionality of parvalbumin neurons in the prefrontal cortex. "Given these promising results, the same compound will be tested in humans as an additional treatment in the early phase of the disease. It’s an important step forward!" says Inès Khadimallah with a smile.
Towards individualized treatment thanks to patient stratification
By analysing the blood of patients diagnosed with psychosis, Do's group was able to determine the levels of miR137 and COX6A2 in the brain. Using these two molecules as biomarkers, they succeeded in demonstrating that among the great heterogeneity of schizophrenia patients there are two major and distinct groups, those with and those without mitochondrial impairments. In addition, the mitochondrial abnormalities are associated with cognitive impairments and the corresponding clinical symptoms: loss of autonomy and reduced social skills. "Patients suffering from a mitochondrial deficiency have more severe clinical symptoms than others", explains Inès Khadimallah.
The study thus revealed two biomarkers that would make it possible to accurately select patients who are likely to benefit from a treatment targeting the deregulation of cerebral mitochondria. "Our work paves the way for a precise diagnosis and an early, individualised treatment for people with a high clinical risk", concludes Kim Do.